CD147 and Corneal Wound Repair

CD147和角膜伤口修复

• 批准号: 8816764
• 负责人: Pablo Argueso
• 金额: $ 50.64万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8816764
• 关键词: Address; Affinity; Area; Avidity; Binding; Biological; Biological Process; Cell Communication; Cell Surface Receptors; Cell surface; Cells; Chronic; Clinical Management; Complex; Cornea; Corneal Injury; Data; Defect; Development; Epithelial; Epithelial Cells; Epithelium; Experimental Models; Extracellular Matrix; Failure; Family; Feedback; Frequencies; Galactose Binding Lectin; Galactosides; Galectin 3; Gene Expression Profile; Gene Expression Profiling; Healed; Homo; Human; Infection; Inflammation; Injury; Integral Membrane Protein; Intervention; Knockout Mice; Lead; Lectin; Link; MMP9 gene; Matrix Metalloproteinases; Mediating; Metalloproteases; Molecular; Movement; Mus; N-terminal; Ophthalmologist; Pathogenesis; Pathway interactions; Patients; Peptide Hydrolases; Physiological; Play; Polysaccharides; Process; Production; Proteins; Recurrence; Regulation; Research; Role; Site-Directed Mutagenesis; Small Interfering RNA; Structure; Therapeutic; Time; Tissues; Tunicamycin; Up-Regulation; Wound Healing; cell motility; corneal epithelium; corneal repair; glycosylation; healing; human tissue; inhibitor/antagonist; insight; migration; mouse model; neoplastic cell; novel; novel therapeutic intervention; prevent; public health relevance; receptor; wound

DESCRIPTION (provided by applicant): The healing process after corneal injury is initiated through the release of a number of proteins that disassemble the epithelial junctions and contribute to the movement of the epithelial sheet to cover the wounded area. Matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade components of the cell surface and extracellular matrix, are central to this process. Barely detected in unwounded cornea, their induction is thought to play a key role during wound healing and in the establishment of chronic wounds. The production and activation of MMPs are tightly regulated by complex mechanisms that include homo-oligomerization of CD147, a heavily N-glycosylated transmembrane protein highly expressed in tumor cells. We recently discovered that CD147 is a novel cell surface counter-receptor for galectin-3, a �alactoside-binding lectin known to cluster cell surface receptors. More importantly, we found that clustering of CD147 by galectin-3 dramatically upregulates MMP9, the primary metalloproteinase synthesized and secreted by corneal epithelial cells migrating to resurface a wound. The long-term objective of this proposal is to determine whether induction of CD147 clustering by galectin-3 is a powerful regulatory mechanism of the physiological and pathological remodeling processes associated with wound repair in the cornea. The following specific aims will address this objective: (1) to investigate te role of CD147 clustering by galectin-3 as modulator of collective cell detachment and cell migration in corneal epithelial cells, and to determine whether degradation of the galectin-3 by MMP9 inhibits CD147 clustering, thereby constituting a negative feedback mechanism to prevent sustained corneal remodeling, (2) to investigate the role of CD147 N-glycosylation in modulating galectin-3 binding affinity, CD147 clustering, and MMP9 induction, and (3) to characterize the biological role of the CD147/galectin-3 complex in mouse models of wound healing and recurrent erosion, and determine whether inhibiting galectin-3 receptor clustering and CD147 function have a therapeutic potential during recurrent epithelial wound healing. This research will explore, for the first time, the molecular mechanism linking glycan dynamics to the biological process by which wounded tissue initiates epithelial cell detachment and migration, and will provide better insight into the pathogenesis of chronic wounds.

描述（由申请人提供）：角膜损伤后的愈合过程是通过释放许多蛋白质来启动的，这些蛋白质分解上皮连接并有助于上皮片的移动以覆盖受伤区域。基质金属蛋白酶 (MMP) 是降解细胞表面和细胞外基质成分的蛋白水解酶家族，是这一过程的核心。在未受伤的角膜中几乎检测不到，它们的诱导被认为在伤口愈合和慢性伤口形成过程中发挥着关键作用。 MMP 的产生和激活受到复杂机制的严格调控，其中包括 CD147 的同源寡聚化，CD147 是一种在肿瘤细胞中高度表达的高度 N-糖基化的跨膜蛋白。我们最近发现 CD147 是 galectin-3 的一种新型细胞表面反受体，galectin-3 是一种乳糖苷结合凝集素，已知可聚集 细胞表面受体。更重要的是，我们发现半乳糖凝集素-3对CD147的聚集显着上调MMP9，MMP9是由角膜上皮细胞迁移以重新形成伤口表面时合成和分泌的主要金属蛋白酶。该提案的长期目标是确定半乳糖凝集素 3 诱导 CD147 簇是否是与角膜伤口修复相关的生理和病理重塑过程的强大调节机制。以下具体目标将实现这一目标：（1）研究半乳糖凝集素 3 的 CD147 聚类作为角膜上皮细胞中集体细胞脱离和细胞迁移的调节剂的作用，并确定 MMP9 降解半乳糖凝集素 3 是否会抑制 CD147 聚类，从而构成防止持续角膜重塑的负反馈机制，（2）研究半乳糖凝集素 3 的作用。 CD147 N-糖基化在调节半乳糖凝集素 3 结合亲和力、CD147 聚类和 MMP9 诱导中的作用，以及 (3) 表征 CD147/半乳糖凝集素 3 复合物在小鼠伤口愈合和复发性糜烂模型中的生物学作用，并确定抑制半乳糖凝集素 3 受体聚类和 CD147 功能在复发性上皮伤口期间是否具有治疗潜力 康复。这项研究将首次探索将聚糖动力学与受伤组织启动上皮细胞脱离和迁移的生物过程联系起来的分子机制，并将为慢性伤口的发病机制提供更好的见解。